Oral pharmaceutical dosage forms comprising a proton pump inhibitor and a NSAID

ABSTRACT

An oral pharmaceutical dosage form comprising an acid susceptible proton pump inhibitor and one or more NSAIDs in a fixed formulation, wherein the proton pump inhibitor is protected by an enteric coating layer. The fixed formulation is in the form of an enteric coating layered tablet, a capsule or a multiple unit tableted dosage form. The multiple unit dosage forms are most preferred. The new fixed formulation is especially useful in the treatment of gastrointestinal side-effects associated with NSAID treatment

FIELD OF THE INVENTION

[0001] The present invention is related to new oral pharmaceuticalpreparations especially for use in the treatment and prophylaxis ofgastrointestinal disorders associated with the use of Non SteroidalAntiinflammatory Drugs (NSAIDs). The present preparations comprise anacid susceptible proton pump inhibitor in combination with one or moreNSAID(s) in a new fixed unit dosage form, especially a tableted dosageform. Furthermore, the present invention refers to a method for themanufacture of such preparations and the use of such preparations inmedicine.

BACKGROUND OF THE INVENTION

[0002] NSAIDs including acetyl salicylic acid are among the mostcommonly prescribed and used drugs world-wide. Despite the therapeuticbenefits of NSAIDs, their use is frequently limited by an increased riskof gastrointestinal side-effects, mainly upper gastrointestinalside-effects like peptic ulceration and dyspeptic symptoms.

[0003] The relative risk of developing a gastric ulcer during NSAIDtreatment is increased by a factor 40-50, and the relative risk ofdeveloping a duodenal ulcer is increased by a factor 8-10 (McCarty D M.Gastroenterology 1989;96:662). The relative risk of developing an ulcercomplication like bleeding and perforation of the stomach is increasedby a factor 1.5-5 (Hawkey C. BMJ 1990;300:278). Further, dyspepticsymptoms are experienced in 30-60% of those on NSAID treatment (LarkaiEN.AmJGas 1987;82:1153).

[0004] In the UK, NSAIDs account for 25% of all reports of adverse drugreactions received by the authorities, and the corresponding figure is21% in USA. Therefore, therapies which avoid gastrointestinalside-effect caused by NSAIDs is requested.

[0005] Attempts to modify the NSAID structure in order to prevent suchside-effects have so far been less successful. The most promisingsolution to the problem of healing and preventing NSAID associated uppergastrointestinal problems like ulcers and dyspeptic symptoms in patientswith a need for continuous NSAID treatment is to combine the NSAIDtreatment with an anti-ulcer drug approved for the healing and/orprophylaxis of NSAID associated gastrointestinal side-effects such asprostaglandin analogues, H₂-receptor antagonists or proton pumpinhibitors.

[0006] Established risk factors for developing NSAID associated uppergastrointestinal side-effects and complications are for instance highage, previous peptic ulcer and/or bleeding, high dose of NSAID,co-therapy with steroids, and co-therapy with anticoagulants. Thismeans, that for example fragile and elderly patients tolerating acomplication like bleeding or perforation badly, should receiveprophylactic treatment in connection with their NSAID treatment.

[0007] NSAIDs are mainly used for the treatment of chronic diseases likerheumatoid arthtritis and osteoarthritis, which are most often seen inthe elderly population. Compliance is especially important in elderlyand fragile patients, who have the highest risk of developing alife-threatening complication to NSAID treatment like bleeding orperforation. It is known that 50% of all peptic ulcer deaths occur inNSAID users and that 68% of these are >75 years old (Catford:HealthTrends 1986;18:38). This is confirmed in another study concluding, thatNSAID-related deaths occur primarily in those >75 years of age (Guess. JClin Epidemiol 1988;41:35). The importance of compliance is furthersupported by the finding, that a majority of peptic ulcers associatedwith NSAID treatment are asymptomatic until the event.

[0008] Omeprazole being a well known proton pump inhibitor has beenshown to be able to prevent gastric and duodenal erosions in healthyvolunteers during treatment with acetyl salicylic acid. Clinical studieshave shown, that omeprazole heals gastric as well as duodenal ulcers asfast and effectively in patients on continuous NSAID treatment as innon-NSAID users (Walan A. N Engl J Med 1989;320:69). These results havebeen the basis for an amendment to the dose recommendation for the useof omeprazole in healing of gastric and duodenal ulcers duringcontinuous NSAID treatment approved by regulatory authorities in UK andSweden.

[0009] Recent studies confirm, that omeprazole significantly reduces therisk of developing gastric ulcers, duodenal ulcers and also dyspepticsymptoms in patients on continuous NSAID treatment.

[0010] EP 0 426 479 describes tablet compositions comprising a NSAIDsuch as ibuprofen and a gastric acid inhibiting drug, such as cimetidinetc. No specific arrangement is taken to avoid degradation if thegastric acid inhibitor is an acid susceptible compound, such as a protonpump inhibitor.

[0011] In proposed therapies comprising NSAID(s) and an acid susceptibleproton pump inhibitor the different active substances are administredseparately. It is well known that patient compliance is a main factor inreceiving a good result in medical treatments. Therefore, administrationof two or even more different tablets to the patient is not convenientor satisfactory to achieve the most optimal results. The presentinvention now provides new oral dosage forms comprising two or moredifferent active substances combined in one fixed unit dosage form,preferably a tablet.

[0012] Some anti-ulcer drugs such as proton pump inhibitors aresusceptible to degradation/transformation in acid reacting and neutralmedia as mentioned above. In respect of the stability properties, it isobvious that the one of the active substances being a proton pumpinhibitor must be protected from contact with acidic gastric juice by anenteric coating layer. There are different enteric coating layeredpreparations of proton pump inhibitors described in the prior art, seefor example U.S. Pat. No. 4,786,505 (AB Hässle) comprising omeprazole.

[0013] There are problems to produce a fixed unit dosage form comprisinga rather high amount of active substance. Active substances withdifferent physical properties combined in the same preparation givefurther problems. Preparation of a multiple unit tableted dosage formarises specific problems when enteric coating layered pellets containingthe acid susceptible proton pump inhibitor are compressed into tablets.If the enteric coating layer does not withstand the compression of thepellets into a tablet, the susceptible active substance will bedestroyed upon administration by penetrating acidic gastric juice, i.e.the acid resistance of the enteric coating layer of the pellets will notbe sufficient in the tablet after compression.

SUMMARY OF THE INVENTION

[0014] The present invention provides oral, fixed unit dosage forms,i.e. multiple unit tableted dosage forms, enteric coating layeredtablets, multilayered tablets or capsules filled with more than onepharmaceutically active compound. The active compounds are preferably anacid susceptible proton pump inhibitor in combination with one or moreNSAIDs and wherein at least the proton pump inhibitor is protected by anenteric coated layer. These new dosage forms will simplify the regimenand improve the patient compliance.

DESCRIPTION OF THE FIGURES

[0015]FIG. 1 illustrates a cross-section of a multiple unit tableteddosage form comprising an acid susceptible proton pump inhibitor in theform of enteric coating layered pellets (1) in admixture with a fastdisintegrating granulate comprising a NSAID (2). The tablet is coveredby an filmcoating layer (13).

[0016]FIG. 2 illustrates a cross-section of a multiple unit tableteddosage form comprising an acid susceptible proton pump inhibitor in theform of enteric coating layered pellets (1) and a NSAID in the form ofcyclodextrin complex (3) included in a fast disintegrating granulate(4). The tablet is covered by a filmcoating layer (13).

[0017]FIG. 3 illustrates a cross-section of a tablet with two separatelayers, one layer comprises an acid susceptible proton pump inhibitor inthe form of enteric coating layered pellets (1) in admixture withexcipients (5) and the other layer comprises a NSAID (6) included in agelling matrix giving extended release. The separate layers areoptionally separated by a separating layer (12) and the tablet iscovered by a filmcoating layer (13).

[0018]FIG. 4 illustrates a cross-section of a multiple unit tableteddosage form comprising an acid susceptible proton pump inhibitor in theform of enteric coating layered pellets (1) and a NSAID in the form ofenteric coating layered pellets (7) in admixture with excipients (5).The tablet is covered by a filmcoating layer (13).

[0019]FIG. 5 illustrates a cross-section of an enteric coating layeredtablet comprising an acid susceptible proton pump inhibitor (8) inadmixture with one or more NSAID(s) (9) and excipients (5). The tabletis covered by an enteric coating layer (1 1) and optionally a separatinglayer (10) is layered in between the tablet core and the enteric coatinglayer.

[0020]FIG. 6 illustrates a tablet comprising an acid susceptible protonpump inhibitor in the form of enteric coating layered pellets (1) inadmixture with a fast disintegrating granulate (4) in a tablet core,surrounded by a coating layer comprising a NSAID substance/granulation(2). The tablet is covered by a pigmented filmcoating layer (13).

DETAILED DESCRIPTION OF THE INVENTION

[0021] One object of the invention is to provide an oral, multiple unittableted dosage form comprising an anti-ulcer drug, preferably an acidsusceptible proton pump inhibitor in the form of individually entericcoating layered units, together with one or more NSAIDs and tabletexcipients compressed into a tablet The enteric coating layer(s)covering the individual units of the acid susceptible proton pumpinhibitor has properties such that the compression of the units into atablet does not significantly affect the acid resistance of theindividually enteric coating layered units. Furthermore, the multipleunit tableted dosage form provides a good stability to the activesubstances during long-term storage.

[0022] Alternatively, the prepared tablet has separate layers, one layerthat comprises the acid susceptible proton pump inhibitor in the form ofcompressed enteric coated layered units and another layer that comprisesthe NSAID(s).

[0023] The new fixed dosage form is preferably in the form of a multipleunit tableted dosage form comprising enteric coating layered units ofthe acid susceptible substance and the other active substance(s) in thegranulated material constituting the rest of the compressed tablet, asshown in FIG. 1.

[0024] Alternatively, the different active substances may be intimatelymixed with each other and compressed into a conventional tablet, whichis enteric coating layered, see FIG. 5, or both active substances are inthe form of enteric coating layered pellets compressed into a multipleunit tableted formulation together with preferably fast disintegratinggranules of inactive excipients, as exemplified in FIG. 4.

[0025] Further alternatives are exemplified as multiple unit dosageforms wherein the proton pump inhibitor is in the form of individuallyenteric coating layered units and the NSAID(s) in the form of a) acomplex to obtain improved bioavailability, see FIG. 2, or b) in theform of a gelling matrix resulting in a preparation with extendedrelease of the NSAID(s), see FIG. 3. A further alternative is a multipledosage form with the proton pump inhibitor in the form of individuallyenteric coating layered units compressed into a tablet and thereupon aseparate layer of the NSAID(s) is applied by spray layering on thetablet. The tablet is covered by a pigmented filmcoating layer toprotect the NSAID(s), see FIG. 6, because some NSAID(s) are lightsensitive and require a light protecting layer.

[0026] In still another alternative, the different active substances aredry mixed and filled into a capsule. In the latter preparation the acidsusceptible proton pump inhibitor is in the form of enteric coatinglayered units and the NSAID(s) is/are in the form of granules oralternatively in the form of modified release formulated units such asenteric coating layered units or units layered with a controlled releaselayer.

[0027] The NSAID(s) may be formulated in instant release, sustainedrelease or extended release formulations. Alternatively, the componentsmay be formulated in an effervescent formulation. Furthermore, as someNSAID(s) are light sensitive the formulation is preferably lightprotected by a pigmented tablet filmcoating layer, as exemplified inFIG. 6, or by including a pigment in one of the coating layers to beapplied on the tableted dosage form.

[0028] A further object of the invention is to provide a dosage formwhich is divisible, such as divisible tablets.

[0029] Still a further object of the invention is to provide a multipleunit tableted dosage form, which is divisible and easy to handle. Someof the multiple unit tableted dosage forms may be dispersed in aslightly acidic aqueous liquid and can be given to patients withswallowing disorders and in pediatrics. Such a suspension of dispersedunits/pellets of appropriate size can be used for oral administrationand also for feeding through a naso-gastric tube.

[0030] The different active components used in the present dosage formsare defined below.

[0031] Active Substances

[0032] The anti-ulcer drug is preferably an acid susceptible proton pumpinhibitor. Such proton pump inhibitors are for example compounds of thegeneral formula I

[0033] wherein

[0034] N in the benzimidazole moiety means that one of the carbon atomssubstituted by R₆-R₉ optionally may be exchanged for a nitrogen atomwithout any substituents;

[0035] R₁, R₂ and R₃ are the same or different and selected fromhydrogen, alkyl, alkoxy optionally is substituted by fluorine,alkylthio, alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen,phenyl and phenylalkoxy;

[0036] R₄ and R₅ are the same or different and selected from hydrogen,alkyl and aralkyl;

[0037] R₆′ is hydrogen, halogen, trifluoromethyl, alkyl and alkoxy;

[0038] R₆-R₉ are the same or different and selected from hydrogen,alkyl, alkoxy, halogen, haloalkoxy, alkylcarbonyl, alkoxycarbonyl,oxazolyl, trifluoroalkyl, or adjacent groups R₆-R₉ form ring structureswhich may be further substituted;

[0039] R₁₀ is hydrogen or forms an alkylene chain together with R₃ and

[0040] R₁₁ and R₁₂ are the same or different and selected from hydrogen,halogen or alkyl, alkyl groups, alkoxy groups and moities thereof, theymay be branched or straight C₁-C₉-chains or comprise cyclic alkylgroups, such as cycloalkyl-alkyl.

[0041] Examples of proton pump inhibitors according to formula I are

[0042] The acid susceptible proton pump inhibitors used in the dosageforms of the invention may be used in their neutral form or in the formof an alkaline salt, such as for instance the Mg²⁺, Ca²⁺, Na⁺, K⁺ or Li⁺salts, preferably the Mg²⁺ salts. Further where applicable, thecompounds listed above may be used in racemic form or in the form of thesubstantially pure enantiomer thereof, or alkaline salts of the singleenantiomers.

[0043] Suitable proton pump inhibitors are for example disclosed inEP-A1-0005129, EP-A1-174 726, EP-A1-166 287, GB 2 163 747 andWO90/06925, WO91/19711, WO91/19712, and further especially suitablecompounds are described in WO95/01977 and WO94/27988.

[0044] A wide variety of NSAIDs may be used in combination with asuitable proton pump inhibitor and optional pharmaceutically acceptableexcipients in the fixed unit dosage form according to the presentinvention. Such NSAIDs include for example propionic acid derivatives,oxicams, acetic acid and acetamide derivatives, salicylic acidderivatives and pyrazolidine derivatives.

[0045] Also future NSAIDs like cyclooxygenase (COX) 2 selective NSAIDsand NO-releasing NSAIDs (de Soldato P, NO-releasing NSAID:s, A new classof safer anti-inflammatory analgesic and anti-pyrretic agents; The IVInternational meeting on side-effects of anti-inflammatory drugs Aug.7-9, 1995) may be included.

[0046] In the following examples of some suitable NSAIDs are listed:Acetyl salicylic acid, indometacin, diclofenac, piroxicam, tenoxicam,ibuprofen, naproxen, ketoprofen, nabumetone, ketorolac, azapropazone,mefenamic acid, tolfenamic acid, sulindac, diflunisal, tiaprofenic acid,podophyllotoxin derivatives, acemetacin, aceclofenac, droxicam,oxaprozin, floctafenine, phenylbutazone, proglumetacin, flurbiprofen,tolmetin and fenbufen.

[0047] The active NSAIDs could be in standard forms or used as salts,hydrates, esters etc. A combination of two or more of the above listeddrugs may be used. Preferable NSAIDs for the new fixed dosage form arediclofenac, ibuprofen, naproxen and piroxicam.

[0048] The preferred multiple unit tableted dosage form comprising aproton pump inhibitor (in the form of a racemat, an alkaline salt or oneof its single enantiomers) and one or more NSAIDs, is characterized inthe following way. Individually enteric coating layered units (smallbeads, granules or pellets) containing the proton pump inhibitor andoptionally containing alkaline reacting substances, are mixed with theNSAID(s) and conventional tablet excipients. Preferably, the NSAID(s)and tablet excipients are in the form of a granulation. The dry mixtureof enteric coating layered units, NSAID granules and optional excipientsare compressed into multiple unit tableted dosage forms. With theexpression “individual units” is meant small beads, granules or pellets,in the following referred to as pellets of the acid susceptible protonpump inhibitor.

[0049] The compaction process (compression) for formulating the multipleunit tableted dosage form must not significantly affect the acidresistance of the enteric coating layered pellets comprising the acidsusceptible proton pump inhibitor. In other words the mechanicalproperties, such as the flexibility and hardness as well as thethickness of the enteric coating layer(s), must secure that therequirements on enteric coated articles in the United StatesPharmacopeia are accomplished in that the acid resistance does notdecrease more than 10% during the compression of the pellets intotablets.

[0050] The acid resistance is defined as the amount of proton pumpinhibitor in the tablets or pellets after being exposed to simulatedgastric fluid USP, or to 0.1 M HCl (aq) relative to that of unexposedtablets and pellets, respectively. The test is accomplished in thefollowing way. Individual tablets or pellets are exposed to simulatedgastric fluid of a temperature of 37° C. The tablets disintegraterapidly and release the enteric coating layered pellets to the medium.After two hours the enteric coating layered pellets are removed andanalyzed for content of the proton pump inhibitor using High PerformanceLiquid Chromatography (HPLC).

[0051] Further specific components which may be used in the fixed unitdosage forms of the present invention are defined below.

[0052] Core Material—for Enteric Coating Layered Pellets/Units

[0053] The core material for the individually enteric coating layeredpellets can be constituted according to different principles. Seedslayered with the proton pump inhibitor, optionally mixed with alkalinesubstances, can be used as the core material for the further processing.

[0054] The seeds which are to be layered with the proton pump inhibitorcan be water insoluble seeds comprising different oxides, celluloses,organic polymers and other materials, alone or in mixtures orwater-soluble seeds comprising different inorganic salts, sugars,non-pareils and other materials, alone or in mixtures. Further, theseeds may comprise the proton pump inhibitor in the form of crystals,agglomerates, compacts etc. The size of the seeds is not essential forthe present invention but may vary between approximately 0.1 and 2 mm.The seeds layered with the proton pump inhibitor are produced either bypowder or solution/suspension layering using for instance granulation orspray coating layering equipment.

[0055] Before the seeds are layered, the proton pump inhibitor may bemixed with further components. Such components can be binders,surfactants fillers, disintegrating agents, alkaline additives or otherand/or pharmaceutically acceptable ingredients alone or in mixtures. Thebinders are for example polymers such as hydroxypropyl methylcellulose(HPMC), hydroxypropyl-cellulose (HPC), carboxymethylcellulose sodium,polyvinyl pyrrolidone (PVP), or sugars, starches or otherpharmaceutically acceptable substances with cohesive properties.Suitable surfactants are found in the groups of pharmaceuticallyacceptable non-ionic or ionic surfactants such as for instance sodiumlauryl sulfate.

[0056] Alternatively, the proton pump inhibitor optionally mixed withalkaline substances and further mixed with suitable constituents can beformulated into a core material. Said core material may be produced byextrusion/spheronization, balling or compression utilizing conventionalprocess equipment. The size of the formulated core material isapproximately between 0.1 and 4 mm and preferably between 0.1 and 2 mm.The manufactured core material can further be layered with additionalingredients comprising the proton pump inhibitor and/or be used forfurther processing.

[0057] The proton pump inhibitor is mixed with pharmaceuticalconstituents to obtain preferred handling and processing properties anda suitable concentration of the proton pump inhibitor in the finalpreparation. Pharmaceutical constituents such as fillers, binders,lubricants, disintegrating agents, surfactants and otherpharmaceutically acceptable additives may be used.

[0058] Further, the proton pump inhibitor may also be mixed with analkaline, pharmaceutically acceptable substance (or substances). Suchsubstances can be chosen among, but are not restricted to substancessuch as the sodium, potassium, calcium, magnesium and aluminium salts ofphosphoric acid, carbonic acid, citric acid or other suitable weakinorganic or organic acids; aluminium hydroxide/sodium bicarbonatecoprecipitate; substances normally used in antacid preparations such asaluminium, calcium and magnesium hydroxides; magnesium oxide orcomposite substances, such as Al₂O₃.6MgO.CO₂.12H₂O,(Mg₆Al₂(OH)₁₆CO₃.4H₂O), MgO.Al₂O₃.2SiO₂.nH₂O or similar compounds;organic pH-buffering substances such as trihydroxymethylaminomethane,basic amino acids and their salts or other similar, pharmaceuticallyacceptable pH-buffering substances.

[0059] Alternatively, the aforementioned core material can be preparedby using spray drying or spray congealing technique.

[0060] Enteric Coating Layer(s)

[0061] Before applying the enteric coating layer(s) onto the corematerial in the form of individual pellets, the pellets may optionallybe covered with one or more separating layer(s) comprisingpharmaceutical excipients optionally including alkaline compounds suchas pH-buffering compounds. Tis/these separating layer(s), separate(s)the core material from the outer layers being enteric coating layer(s).This/these separating layer(s) protecting the core material of protonpump inhibitor should be water soluble br rapidly disintegrating inwater.

[0062] The separating layer(s) can be applied to the core material bycoating or layering procedures in suitable equipments such as coatingpan, coating granulator or in a fluidized bed apparatus using waterand/or organic solvents for the coating process. As an alternative theseparating layer(s) can be applied to the core material by using powdercoating technique. The materials for the separating layers arepharmaceutically acceptable compounds such as, for instance, sugar,polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinylacetate, hydroxypropyl cellulose, methylcellulose, ethylcellulose,hydroxypropyl methyl cellulose, carboxymethylcellulose sodium, watersoluble salts of enteric coating polymers and others, used alone or inmixtures. Additives such as plasticizers, colorants, pigments, fillersanti-tacking and anti-static agents, such as for instance magnesiumstearate, titanium dioxide, talc and other additives may also beincluded into the separating layer(s).

[0063] When the optional separating layer, is applied to the corematerial it may constitute a variable thickness. The maximum thicknessof the separating layer(s) is normally only limited by processingconditions. The separating layer may serve as a diffusion barrier andmay act as a pH-buffering zone. The pH-buffering properties of theseparating layer(s) can be further strengthened by introducing into thelayer(s) substances chosen from a group of compounds usually used inantacid formulations such as, for instance, magnesium oxide, hydroxideor carbonate, aluminium or calcium hydroxide, carbonate or silicate;composite aluminium/magnesium compounds such as, for instanceAl₂O₃.6MgO.CO₂.12H₂O, (Mg6Al₂(OH)₁₆CO₃.4H₂O), MgO.Al₂O₃.2SiO₂.nH₂O,aluminium hydroxide/sodium bicarbonate coprecipitate or similarcompounds; or other pharmaceutically acceptable pH-buffering compoundssuch as, for instance the sodium, potassium, calcium, magnesium andaluminium salts of phosphoric, carbonic, citric or other suitable, weak,inorganic or organic acids; or suitable organic bases, including basicamino acids and salts thereof. Talc or other is compounds may be addedto increase the thickness of the layer(s) and thereby strengthen thediffusion barrier. The optionally applied separating layer(s) is notessential for the invention. However, the separating layer(s) mayimprove the chemical stability of the active substance and/or thephysical properties of the novel multiple unit tableted dosage form.

[0064] Alternatively, the separating layer may be formed in situ by areaction between an enteric coating polymer layer applied on the corematerial and an alkaline reacting compound in the core material. Thus,the separating layer formed comprises a water soluble salt formedbetween the enteric coating layer polymer(s) and an alkaline reactingcompound which is in the position to form a salt.

[0065] One or more enteric coating layers are applied onto the corematerial or onto the core material covered with separating layer(s) byusing a suitable coating technique. The enteric coating layer materialmay be dispersed or dissolved in either water or in suitable organicsolvents. As enteric coating layer polymers one or more, separately orin combination, of the following can be used, e.g. solutions ordispersions of methacrylic acid copolymers, cellulose acetate phthalate,hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcelluloseacetate succinate, polyvinyl acetate phthalate, cellulose acetatetrimellitate, carboxymethylethylcellulose, shellac or other suitableenteric coating polymer(s).

[0066] The enteric coating layers contain pharmaceutically acceptableplasticizers to obtain the desired mechanical properties, such asflexibility and hardness of the enteric coating layers. Suchplasticizers are for instance, but not restricted to triacetin, citricacid esters, phthalic acid esters, dibutyl sebacate, cetyl alcohol,polyethylene glycols, polysorbates or other plasticizers.

[0067] The amount of plasticizer is optimized for each enteric coatinglayer formula, in relation to selected enteric coating layer polymer(s),selected plasticizer(s) and the applied amount of said polymer(s), insuch a way that the mechanical properties, i.e. flexibility and hardnessof the enteric coating layer(s), for instance exemplified as Vickershardness, are adjusted so that the acid resistance of the pelletscovered with enteric coating layer(s) does not decrease significantlyduring compression of pellets into tablets. The amount of plasticizer isusually above 10% by weight of the enteric coating layer polymer(s),preferably 15-50% and more preferably 20-50%. Additives such asdispersants, colorants, pigments polymers e.g. poly (ethylacrylat,methylmethacrylat), anti-tacking and anti-foaming agents may also beincluded into the enteric coating layer(s). Other compounds may be addedto increase film thickness and to decrease diffusion of acidic gastricjuices into the acid susceptible material. To protect the acidsusceptible substance, the proton pump inhibitor, and to obtain anacceptable acid resistance of the dosage form according to theinvention, the enteric coating layer(s) constitutes a thickness ofapproximately at least 10 μm, preferably more than 20 μm. The maximumthickness of the applied enteric coating is normally only limited byprocessing conditions and the desired dissolution profile.

[0068] The enteric coating layer may also be used for layering of theNSAID(s). Alternatively, the enteric coating layer described above mayalso be used for an enteric coating layer of conventional tabletscomprising a composition of a proton pump inhibitor and one or moreNSAIDs, optionally the prepared tablet core also is covered by one ofthe separating layers described above to separate the tablet core fromthe enteric coating layer.

[0069] Over-Coating Layer

[0070] Pellets covered with enteric coating layer(s) may further becovered with one or more over-coating layer(s). The over-coatinglayer(s) should be water soluble or rapidly disintegrating in water. Theover-coating layer(s) can be applied to the enteric coating layeredpellets by coating or layering procedures in suitable equipments such ascoating pan, coating granulator or in a fluidized bed apparatus usingwater and/or organic solvents for the coating or layering process. Thematerials for over-coating layers are chosen among pharmaceuticallyacceptable compounds such as, for instance sugar, polyethylene glycol,polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate,hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropylmethyl cellulose, carboxymethylcellulose sodium and others, used aloneor in mixtures. Additives such as plasticizers, colorants, pigments,fillers, anti-tacking and anti-static agents, such for instancemagnesium stearate, titanium dioxide, talc and other additives may alsobe included into the over-coating layer(s). Said over-coating layer mayfurther prevent potential agglomeration of enteric coating layeredpellets, further it may protect the enteric coating layer towardscracking during the compaction process and enhance the tabletingprocess. The maximum thickness of the applied over-coating layer(s) isnormally limited by processing conditions and the desired dissolutionprofile. The over-coating layer may also be used as a tablet filmcoatinglayer.

[0071] NSAID Preparation

[0072] The active substance(s) in the form of one or more NSAIDsubstances is dry mixed with inactive excipients, wherein one or more ofthe excipients optionally is a disintegrant. The mixture is wet massedwith a granulation liquid. The wet mass is dried preferably to a loss ondrying of less than 3% by weight Thereafter the dry mass is milled to asuitable size for the granules, such as smaller than 4 mm, andpreferably smaller than 1 mm. Suitable inactive excipients for the NSAIDgranulation are for instance, sodium starch glycolate, corn starch,crosslinked polyvinylpyrrolidone, low substituted hydroxypropylcellulose, microcrystalline cellulose, mannitol and colloidal silicondioxide an hydrous (Aerosil®) and the like. The dry mixture comprisingNSAID(s) is mixed with a suitable granulation liquid comprising forinstance, polyvinyl pyrrolidone, hydroxypropyl-cellulose, polyethyleneglycol, hydroxypropyl cellulose and optionally wetting agents, such assodium lauryl sulphate, dissolved in purified water or a suitablealcohol or a mixture thereof.

[0073] Mechanical treatment may in some cases be used to form a complexbetween the NSAID(s) and a complex forming agent, such asbeta-hydroxypropyl cyclodextrin like in Example 3 below. Cyclodextrincomplexes of NSAID(s) are shown to have an increased bioavailability ofthe NSAID(s), see for instance Drug Dev. Ind. Pharm. 19(7),843-852,(1993).

[0074] Further, the NSAID may be mixed with a gelling agent during thegranulation, such as hydrophilic polymer(s). Suitable gellinghydrophilic polymers are for instance hydroxypropylmethylcellulose,polyoxyethylen (polyethylene glycol), hydroxypropylcellulose,hydroxyethylcellulose and xantan. The granules may also comprisebuffering substances. See for instance Example 4 below. Some NSAIDsirritate the gastric mucosa and benefit from a protecting entericcoating layer and may be formulated as enteric coating layered pellets.

[0075] Multiple Unit Tablets

[0076] The enteric coating layered pellets comprising a proton pumpinhibitor are mixed with the granules comprising NSAID(s) and tabletexcipients. The mixture is compressed into a multiple unit tableteddosage form. The compressed tablet is optionally covered with afilmforming agent(s) to obtain a smooth surface of the tablet andfurther enhance the stability of the tablet during packaging andtransport Such a tablet filmcoating layer may further comprise additivessuch as anti-tacking agents, colorants and pigments or other additivesto obtain a tablet of good appearance and with a light-protection forlight sensitive components.

[0077] The enteric coated pellets with or without an over-coat and theNSAID granules are mixed with tablet excipients such as fillers,binders, disintegrants, lubricants and other pharmaceutically acceptableadditives and compressed into tablets. Suitable lubricants for thetableting process are for instance sodium stearyl fumarate, magnesiumstearate and talc.

[0078] Alternatively, the NSAID(s) may be dry mixed with the entericcoating layered pellets comprising the proton pump inhibitor optionallytogether with inactive excipients and compressed into tablets (directcompression), or the different active substances may be formulated indifferent layers, optionally the NSAID(s) in the form of a layer with acontrolled release.

[0079] Further, both the NSAID(s) and the proton pump inhibitor in theform of enteric coating layered pellets may be mixed with inactivetablet excipients and compressed into a tablet. The compressed tablet isoptionally covered by a tablet filmcoating layer to obtain a tablet ofgood appearance.

[0080] As a further alternative a multiple unit tableted dosage formcomprising the proton pump inhibitor is spray coating layered by asuspension or solution comprising the NSAID(s). The prepared tablet isthereafter covered by a pigmented tablet filmcoating layer.

[0081] The fraction of enteric coating layered pellets constitutes lessthan 75% by weight of the total tablet weight and preferably less than60%. By increasing the amount of the granules comprising the NSAID(s)the fraction of enteric coating layered proton pump inhibitor pellets inthe multiple unit dosage form may be reduced. By choosing small entericcoating layered pellets in the formulation according to the presentinvention, the number of pellets in each tablet can be held high whichin turn makes the tablet divisible with retained dosing accuracy.

[0082] Thus, the preferred multiple unit tablet formulation consists ofenteric coating layered pellets containing one active substance in theform of an acid susceptible proton pump inhibitor, optionally mixed withalkaline reacting compound(s), compressed into tablet together withgranules containing NSAID(s) and optionally tablet excipients. Theaddition of an alkaline reacting material to the proton pump inhibitoris not necessary, in any sense but such a substance may further enhancethe stability of the proton pump inhibitor or some of the alkalinereacting compounds may react in situ with the enteric coating materialto form a separating layer. The enteric coating layer(s) is making thepellets of the dosage form insoluble in acidic media, butdisintegrating/dissolving in near neutral to alkaline media such as, forinstance the liquids present in the proximal part of the smallintestine, where dissolution of the proton pump inhibitor is desired.The NSAID(s) may be released in the stomach. The enteric coating layeredpellets may further be covered with an overcoating layer before beingformulated into the tablet and they may also contain one or moreseparating layer(s) in between the core material and the enteric coatinglayer.

[0083] Process

[0084] The process for the manufacture of the dosage form represents afurther aspect of the invention. After formulation of the pellets byspray coating or layering of the proton pump inhibitor onto seeds, or byextrusion/spheronization or granulation, e.g. rotor granulation ofhomogeneous pellets, the pellets are first optionally covered with theseparating layer(s) and then with the enteric coating layer(s) or aseparating layer is spontaneously developed in situ between an alkalinecore material and the enteric coating layer material. The coating iscarried out as described above and in the accompanying examples. Thepreparation of the granules comprising the NSAID(s) and enteric coatinglayered NSAID pellets are also described above and in the examples. Thepharmaceutical processes can preferably be completely water-based.

[0085] The enteric coating layered pellets, with or without anover-coat, are mixed with the prepared granules, tablet excipients andother pharmaceutical acceptable additives and compressed into tablets.Alternatively, the different active substances in the form of powdersmay be intimately dry mixed with tablet excipients, wet massed andcompressed into conventional tablets before applying an optionalseparating layer and an enteric coating layer. The NSAID(s) may also beincorporated in a coating layer applied onto a multiple unit dosage formcomprising the proton pump inhibitor, or the NSAID(s) and proton pumpinhibitor in the form of enteric coating layered pellets are mixed withinactive tablet excipients and compressed into a multiple unit tableteddosage form.

[0086] The different active substances may also be formulated intodifferent layers, wherein the layer comprising the NSAID(s) may be inthe form of a control release preparation. As a further alternative, theacid susceptible proton pump inhibitor in the form of enteric coatinglayered pellets may be filled in a capsule together with the NSAID(s) inthe form of granules or enteric coating layered pellets, and optionallymixed with pharmaceutical excipients.

[0087] Use of the Preparation

[0088] The dosage forms according to the invention are especiallyadvantageous in the treatment of gastrointestinal side-effects caused byNSAID(s), such as in a continuous treatment with NSAID(s). The newdosage forms are administered one to several times a day, preferablyonce or twice daily. The typical daily dose of the active substancesvaries and will depend on various factors such as the individualrequirements of the patients, the mode of administration and disease. Ingeneral each dosage form will comprise 0,1-200 mg of the proton pumpinhibitor and 0.1-1,000 mg of the NSAID(s). Preferably, each dosage formwill comprise 10-80 mg of the proton pump inhibitor and 10-800 mg of theNSAID(s), and more preferably 10-40 mg of proton pump inhibitor and10-500 mg of the NSAID(s), respectively. Especially preferredcombinations comprise for instance 10 mg omeprazole together with 50 mgdiclofenac, 10 mg omeprazole and 250 mg naproxen, 10 mg omeprazole and10 mg piroxicam, or 10 mg omeprazole and 400 mg ibuprofen.

[0089] The multiple unit tablet preparation may also be suitable fordispersion in an aqueous liquid with slightly acidic pH-value beforebeing orally administered or fed through a naso-gastric tube.

[0090] The invention is illustrated more in detail in the followingexamples.

EXAMPLES Example 1

[0091] Fast disintegrating multiple unit tableted dosage form comprisingmagnesium omeprazole and ibuprofen. Core material Magnesium omeprazole12.00 kg Non-pareil cores 12.00 kg Hydroxypropyl methylcellulose  1.8 kgWater purified  35.4 kg Separating layer Core material (acc. to above)23.50 kg Hydroxypropyl cellulose  2.35 kg Talc  4.03 kg MagnesiumStearate  0.34 kg Water purified 48.00 kg Enteric coating layer Pelletswith sep layer (acc. to above) 29.00 kg Methacrylic acid copolymer (30%suspension) 38.70 kg Triethyl citrate  3.48 kg Mono- and diglycerides(NF)  0.58 kg Polysorbate 80  0.06 kg Water purified 22.68 kgOver-coating layer Enteric coating layered pellets (acc. to above)  44.7kg Hydroxypropyl methylcellulose  0.58 kg Mg-Stearate 0.017 kg Waterpurified  11.6 kg Tablets mg/tablet Over-coated pellets comprisingomeprazole 47.85 Ibuprofen 400 Microcrystalline cellulose (MCC) 273.6Polyvinylpyrrolidone cross-linked 100.4 Polyvinylpyrrolidone K-25 33.3Sodium laurylsulphate 26.7 Water purified 297 Sodium stearyl fumarate4.0

[0092] Suspension layering was performed in a fluid bed apparatus.Magnesium omeprazole was sprayed onto inert non-pareil cores from awater suspension containing the dissolved binder.

[0093] The prepared core material was coating layered with a separatinglayer in a fluid bed apparatus with a hydroxypropyl cellulose solutioncontaining talc and magnesium stearate. The enteric coating layerconsisting of methacrylic acid copolymer, mono- and diglycerides,triethylcitrate and polysorbate was sprayed onto the pellets (layeredwith a separating layer) in a fluid bed apparatus. In the same ofapparatus the enteric coating layered pellets were coated withhydroxypropyl methylcellulose/Mg-Stearate suspension. The obtainedpellets were classified by sieving.

[0094] Tablet granulation liquid was made by dissolving 26.7 parts ofsodium laurylsulphate and 33.3 parts of polyvinylpyrrolidone K-25 in 267parts of purified water. 400 parts of ibuprofen, 226 parts of the MCCand 10.4 parts of the cross-linked polyvinylpyrrolidone were dry-mixed.The granulating liquid was added to the powder mixture and the masswet-mixed. 30 parts of water was added as quantum satis.

[0095] The wet mass was dried in an oven at 60° C. for approx. 6 hrs.The dried granules were milled to pass a 0.8 mm sieve.

[0096] The enteric coating layered omeprazole pellets, the milledibuprofen granules, 47.6 parts of MCC, 4.0 parts sodium stearylfumarateand 90 parts of crosslinked polyvinylpyrrolidone were mixed andcompressed to tablets on a tableting machine equipped with 15 mmdiameter punches. Hardness of the 886 mg tablets tested with aSchleuniger apparatus varied between 5.3 and 5.9 kP. Disintegration timetested in simulated gastric juice (USP, without enzymes) was 49-52 sec(n=2).

Example 2

[0097] Fast disintegrating multiple unit tableted dosage form comprisingS-omeprazole magnesium salt and naproxen. Core material S-omeprazolemagnesium 120 g Non-pareil cores 150 g Polysorbat 80  2.4 g Hydroxypropyl methylcellulose  18 g Water purified 562 g Separatinglayer Core material (acc. to above) 200 g Hydroxypropyl cellulose  30 gTalc 51.4 g  Magnesium Stearate  4.3 g  Water purified 600 g Entericcoating layer Pellets with sep layer (acc. to above) 250 g Methacrylicacid copolymer 30% suspension 333.7 g   Triethyl citrate  30 g Mono- anddiglycerides (NF)  5.0 g  Polysorbate 80 (=Tween 80)  0.5 g  Waterpurified 195.8 g   Over-coating layer Enteric coating layered pellets371 g Carboxymethylcellulose-sodium  5.0 g  Water purified 191 g Tabletsmg/tablet Over-coated pellets comprising 55 S-omeprazole Mg-saltNaproxen 250 Microcrystalline cellulose (MCC) 150Hydroxypropylcellulose, low substituted 40 Polyvinylpyrrolidone K-90 5.0Water purified 250

[0098] Suspension layering was performed in a fluid bed apparatus.S-omeprazole magnesium salt was sprayed onto inert sugar seeds(non-pareil cores) from a water suspension containing the dissolvedbinder and polysorbat 80.

[0099] The prepared core material was coating layered by a separatinglayer in a fluid bed apparatus with a hydroxypropyl cellulose solutioncontaining talc and magnesium stearate. The enteric coating layerconsisting of methacrylic acid copolymer, mono- and diglycerides,triethylcitrate and polysorbate was sprayed onto the pellets (withseparating layer) in a fluid bed apparatus. In the same type ofapparatus the enteric coating layered pellets were covered withcarboxymethylcellulose-sodium solution. The over-coating layered pelletswere classified by sieving.

[0100] 5 parts of polyvinylpyrrolidone K-90 was dissolved in 150 partsof purified water to form the granulation liquid. Naproxen, MCC, andlow-substituted hydroxypropyl cellulose were dry-mixed. The granulatingliquid was added to the powder mixture and the mass wet-mixed. 100 partsof water was added as quantum satis.

[0101] The wet mass was dried in an oven at 60° C. for approx. 5-6 hrs.The dried granules were milled to pass a 1.0 mm sieve.

[0102] The enteric coating layered pellets and the milled granules weremixed and compressed to tablets on a tableting machine equipped with18x8.5 mm punches. Average hardness for the 500 mg tablets tested(across the longest axis) with a Schleuniger apparatus was 9.4 kP.Disintegration time tested in purified water at 37° C. was 15-30 sec(n=2).

Example 3

[0103] Fast disintegrating multiple unit tableted dosage form comprisingpantoprazole and piroxicam-β-hydroxypropyl-cyclodextrin. Core materialPantoprazole 100 g Non-pareil cores 200 g Hydroxypropylcellulose LF  25g Water purified 607 g Separating layer Core material (acc. to above)200 g Hydroxypropyl cellulose LF  20 g Talc 34.3 g  Magnesium Stearate 2.9 g  Water purified 400 g Enteric coating layer Pellets with seplayer (acc. to above) 200 g Methacrylic acid copolymer, 30% suspension333 g Triethyl citrate  30 g Mono- and diglycerides (NF)  5 gPolysorbate 80  0.5 g  Water purified 281.5 g   Tablets mg/tabletPellets comprising pantoprazole 133 Piroxicam 20β-hydroxypropyl-cyclodextrin, (90%) 72 Microcrystalline cellulose (MCC)276 Polyvinylpyrrolidone cross-linked 36.8 Water purified ≦2 Sodiumstearylfumarate (SSF) 3.9

[0104] Suspension layering was performed in a fluid bed apparatus.Pantoprazole was sprayed onto inert sugar seeds (non-pareil cores) froma water suspension containing the dissolved binder.

[0105] The prepared core material was coating layered by a separatinglayer in a fluid bed apparatus with a hydroxypropyl cellulose solutioncontaining talc and magnesium stearate. The enteric coating layerconsisting of methacrylic acid copolymer, mono- and diglycerides,triethylcitrate and polysorbate was sprayed onto the pellets (with aseparating layer) in a fluid bed apparatus. The pellets were classifiedby sieving.

[0106] The piroxicam was added to β-hydroxypropyl-cyclodextrin duringmechanical treatment and moisturization with the water. The mass wasdried in a drying oven at 50° C. and then milled to pass a 0.8 mm sieve.

[0107] The piroxicam-β-hydroxypropyl-cyclodextrin, the MCC, thecross-lined polyvinylpyrrolidone and the SSF were dry-mixed andthereafter this mixture was mixed with the pantoprazole pellets.

[0108] Compression to tablets was done on a tableting machine equippedwith 18×8.5 mm punches. Average hardness for the, 577 mg tablets testedwith a Schleuniger apparatus was 16.7 kP with variation between 14.8 and18.7 kP, measurement taken along the longest axis. Disintegration timetested in water was approx. 4 minutes.

[0109] The tablets were coated with a pigmented dispersion like in Ex.7.

Example 4

[0110] Two-layered tablet dosage form with fast disintegrating parthaving 20 mg of lansoprazole in the form of enteric coated pelletscomprised in one layer, and the other layer being an extended releasepart designed as a hydrophilic gel matrix comprising 250 mg of naproxen.

[0111] Lansoprazole Enteric Coated Pellets Core material Lansoprazole400 g Non-pareil cores 400 g Hydroxypropyl methylcellulose  80 g Sodiumlaurylsulphate  3 g Water purified 1360 g  Sub-coating Core material(acc. to above) 100 g Hydroxypropyl methylcellulos  9 gPolyethyleneglycol 6000  1 g Talc  18 g Ethanol 95% 250 g Water purified250 g Enteric coating Sub-coated pellets (acc. to above) 100 gHydroxypropyl methylcellulose phtalate 39.9 g  Acetyltributyl citrate  8g Cetanol  2.1 g  Ethanol 95% 162 g Acetone 378 g

[0112] Suspension layering was performed in a fluid bed apparatus.Lansoprazole was sprayed onto inert non-pareil cores from a watersuspension containing the dissolved binder and the wetting agent.

[0113] The prepared core material was sub-coated in a Wurster equippedfluid bed apparatus with the talc suspended in a HPMC/PEG-solution. PEGalso have a function as plasticizer for the HPMC.

[0114] Enteric coating was performed in the same equipment with asolution in organic solvents of the materials forming the enteric layer.Tablets mg/tablet Pellets comprising lansoprazole 94 Microcrystallinecellulose 181.8 Polyvinyl pyrrolidone cross-linked 18.2 Naproxen 250Polyoxyethylene (mwt appr. 4000000) 200 Sodium aluminium silicate 50L-Arginine 190 Ethanol 95% (w/v) approx. 280

[0115] Naproxen, Polyox WSR 301®, L-Arginin and sodium aluminiumsilicate were dry-mixed. The granulating liquid, ethanol, was added tothe powder mixture and the mass wet-mixed. The wet mass was dried in anoven at 60° C. for approx. 8 hrs. The dried granules were milled to passa 1.0 mm sieve.

[0116] Tablet compression was made by first pre-compressing 690 mg ofthe naproxen-containing granules and then filling 281 mg of a mixtureconsisting of 81 mg lansoprazole pellets plus 181.8 mg of MCC and 18.2mg of crosslinked polyvinylpyrrolidone per tablet, on top. Thesematerials were then compressed together to give the two-layered tabletson a Diaf tableting machine equipped with 9×20 mm punches. Tablethardness tested with a Schleuniger apparatus over the longest axis wasapproximately 14 kP.

[0117] Naproxen dissolution-was tested in phosphate buffer pH 6.8.Obtained results;

[0118] 1 hrs 14% dissolved

[0119] 3 hrs 34% ″

[0120] 5 hrs 58% ″

[0121] 7 hrs 79% ″

[0122] 24 hrs 102% ″

Example 5

[0123] Fast disintegrating multiple unit tableted dosage form comprisingmagnesium omeprazole and piroxicam. Core material (omeprazole) Magnesiumomeprazole  5.00 kg Non-pareil cores 10.00 kg Hydroxypropylmethylcellulose  0.75 kg Water purified 19.65 kg Separating layer(omeprazole) Core material (acc. to above) 14.60 kg Hydroxypropylcellulose  1.46 kg Talc  2.5 kg Magnesium Stearate  0.21 kg Waterpurified  29.2 kg Enteric coating layer (omeprazole) Pellets with seplayer(acc. to above)  9.00 kg Methacrylic acid copolymer (30%suspension) 15.00 kg Triethyl citrate  1.35 kg Mono- and diglycerides(NF)  0.22 kg Polysorbate 80  0.02 kg Water purified  8.8 kgOver-coating layer (omeprazole) Enteric coating layered pellets  9.0 kgHydroxypropyl methylcellulose  0.18 kg Mg-Stearate 0.005 kg Waterpurified  3.6 kg

[0124] Suspension layering was performed in a fluid bed apparatus.Magnesium omeprazole was sprayed onto inert sugar seeds (non-pareilcores) from a water suspension containing the dissolved binder.

[0125] The prepared core material was coating layered by a separatinglayer in a fluid bed apparatus with a hydroxypropyl cellulose solutioncontaining talc and magnesium stearate. The enteric coating layerconsisting of methacrylic acid copolymer, mono- and diglycerides,triethylcitrate and polysorbate was sprayed onto the sub-coated pelletsin a fluid bed apparatus. In the same type of apparatus the entericcoating layered pellets were covered with hydroxypropylmethylcellulose/Mg-Stearate suspension. The over-coating layered pelletswere classified by sieving. Core material (piroxicam) Piroxicammicronized  35 g Sugar seeds 100 g Hydroxypropyl methylcellulose 6 cps 25 g Water purified 250 g Ethanol 99% (w/v) 250 g Enteric coating layer(piroxicam) Piroxicam pellets (acc. to above) 100 g

[0126] were coated with a suspension of the following composition togive a product with a content of 163 mg/g; Hydroxypropyl methylcelluloseacetatesuccinate LF 14.38 parts  Triethyl citrate 2.87 parts Sodiumlaurylsulphate 0.43 parts Talc 4.32 parts Water purified 183.3 parts 

[0127] Suspension layering was performed in a fluid bed apparatus.Micronized piroxicam was sprayed onto inert non-pareil cores from awater suspension containing the dissolved binder.

[0128] The enteric coating layer consisting of hydroxypropylmethylcellulose acetatesuccinate, triethylcitrate, sodium laurylsulphateand talc was sprayed onto the piroxicam pellets in a fluid bedapparatus. Tablets (for 1000 pcs) pellets comprising omeprazole 95.7 g pellets containing piroxicam 122.7 g   Microcrystalline cellulose (MCC)240 g Polyvinylpyrrolidone cross-linked (PVP-XL)  20 gHydroxypropylcellulose, low-substituted (L-HPC)  40 g Sodiumstearylfumarate (SSF)  4.6 g 

[0129] MCC, L-HPC and PVP-XL were mixed together until homogenity. Thetwo kind of enteric coating layered pellets were admixed thereafter.Finally the lubricant SSF was admixed and this mixture was compressed totablets on a tableting machine equipped with 8.5×16 mm punches. Hardnessof the 523 mg tablets tested with a Schleuniger apparatus varied between8 and 9 kP. Disintegration time tested in water 37° C. was less than 1minute.

[0130] The tablets were coated with a pigmented dispersion like inExample 7.

Example 6

[0131] Fast disintegrating enteric coating layered tablet comprisingmagnesium omeprazole and diclofenac. Tablets (for 2000 pcs) Omeprazolemagnesium (corr. 20 mg omeprazole) 45.0 g  Diclofenac sodium (corr. 20mg diclofenac) 43.2 g  Microcrystalline cellulose (MCC) 110 gPolyvinylpyrrolidone cross-linked (PVP-XL)  50 g Hydroxypropylcellulose,low-substituted (L-HPC)  50 g Sodium stearylfumarate (SSF)  8.6 g  Waterpurified approx. 170 g

[0132] The omeprazole, diclofenac, MCC, L-HPC, 30 grams of PVP-XL and5.6 grams of SSF were mixed and then the water was added duringcontinuously mixing. The granulate was dried in a drying oven at 60° C.for approx. 1.5 hours. The dry granulate was milled to pass sieve 1.0mm.

[0133] The milled granules were mixed with 20 grams of PVP-XL and 3.0grams of SSF. This mixture was compressed to 153 mg tablets on atableting machine using 7 mm diameter punches. Average tablet hardnesswas 7.4 kP (n=6). Disintegration time in water 37° C. was 1 minute 20seconds (n=1).

[0134] The tablets were coating layered with a separating layerconsisting of hydroxypropyl methylcellulose (HPMC) and talc in a Wursterequipped fluidized bed. Application of separating layer Tablets 7 mm100.1 g coating dispersion; HPMC 6 cps  5.5 g Talc  1.15 g EtOH 99%(w/v) 46.7 g Water purified  46.7 g

[0135] The obtained coating layered tablets were further coating layeredby an enteric coating layer in the same apparatus. Application ofenteric coating layer Tablets with separating layer  100 g coatingdispersion; Methacrylic acid copolymer as 30% suspension 26.4 g (7.92 gdry mtrl.) Polyethyleneglycole 400  0.9 g Titanium dioxide 0.83 g Ironoxide reddish brown 0.28 g Water purified 55.1 g

[0136] The weight increase of the tablets in the enteric coating stepwas approx. 11 mg/tablet, corresponding to approx. 7% of the weigth ofcharged tablets.

[0137] The pigments in the enteric coating layer provides protectionagainst light

Example 7

[0138] Fast disintegrating multiple unit tableted dosage form comprisingmagnesium omeprazole and an inner coating layer comprisingdiclofenac-sodium and an outer pigmented coating layer providing lightprotection.

[0139] Magnesium omeprazole enteric coating layered pellets from Ex. 5.Tablets mg/tablet Pellets comprising omeprazole 83.3 Microcrystallinecellulose (MCC) 181.4 Polyvinylpyrrolidone cross-linked 3.7 Sodiumstearyl fumarate (SSF) 0.4

[0140] Pellets were prepared as in Example 5.

[0141] The MCC, the cross-linked polyvinylpyrrolidone and the omeprazolecontaining pellets were dry-mixed. Thereafter the SSF was admixed.

[0142] The mixture was compressed to tablets on a tableting machineequipped with 9 mm diameter punches. Hardness of the 269 mg tabletstested with a Schleuniger apparatus varied between 8 and,9 kP.

[0143] The tablets were coated in a fluidized bed with the solutionbelow, until average tablet weight was 298 mg. Diclofenac-sodium  20.0parts by weight HPMC 6 cps  11.4 parts by weight EtOH 99% (w/v) 113.6parts by weight Water purified 113.6 parts by weight

[0144] Finally these tablets were covered with pigmented suspension inthe same equipment. The composition of the coating suspension was; HPMC6 cps   10 parts by weight Polyethylene glycol mwt 6000  2.5 parts byweight TiO₂ 1.83 parts by weight Iron oxide yellow 0.40 parts by weightEtOH 99% (w/v)   85 parts by weight Water purified   85 parts by weight

[0145] Obtained average tablet weight was 303 mg. Disintegration timetested in water 37° C. was less than 4 minutes (n=4).

Example 8

[0146] A capsule formulation comprising magnesium omeprazole andpiroxicam. Capsules Enteric coating layered omeprazole pellets  95.7mg/cap (manufacturing and composition as in Ex. 5) Enteric coatinglayered piroxicam pellets 122.7 mg/cap (manufacturing and composition asin Ex. 5)

[0147] Prepared pellets are filled into hard gelatine capsules, size 3.Optionally a small amount of lubricant is added before filling intocapsules. The amount of omeprazole in each capsule is approx. 20 mg andthe amount of piroxicam is approx. 20 mg.

Example 9

[0148] A capsule formulation- comprising S-omeprazole magnesium salt andnaproxen. Capsules Enteric coating layered pellets 55.2 mg/cap(manufacturing and composition as in Ex. 2) Naproxen granulation  445mg/cap (manufacturing and composition as in Ex. 2)

[0149] Prepared granules and enteric coating layered pellets are filledinto hard gelatine capsules, size 00. Optionally a small amount oflubricant is added before filling into capsules. The amount ofS-omeprazole in each capsule is approx. 10 mg and the amount of naproxenis approx. 250 mg.

Example 10

[0150] Fast disintegrating multiple unit tableted dosage form comprisingmagnesium omeprazole and diclofenac-Na. Core material Magnesiumomeprazole   5 kg Sugar sphere seeds   10 kg Hydroxypropylmethylcellulose 0.75 kg Water purified 19.7 kg Separating layer Corematerial 10.2 kg Hydroxypropyl cellulose 1.02 kg Talc 1.75 kg Magnesiumstearate 0.146 kg  Water purified 21.4 kg Enteric coating layer Pelletscovered with separating layer 11.9 kg Methacrylic acid copolymer (30%suspension) 19.8 kg Triethyl citrate 1.79 kg Mono-and diglycerides (NF)0.297 kg  Polysorbate 80 0.03 kg Water purified 11.64 kg  Over-coatinglayer Enteric coating layered pellets 20.0 kg Hydroxypropylmethylcellulose 0.238 kg  Magnesium stearate 0.007 kg  Water purified6.56 kg Tablets mg/tablet Overcoated pellets comprising omeprazole 82.4Diclofenac-Na 50.0 Microcrystalline cellulose (MCC) 261Polyvinylpyrrolidone cross-linked 5.6 Sodium stearyl fumarate 0.56

[0151] Suspension layering was performed in a fluid bed apparatus.Magnesium omeprazole was sprayed onto sugar sphere seeds from a watersuspension containing the dissolved binder. The size of sugar sphereseeds were in the range of 0.25 to 0.35 mm.

[0152] The prepared core material was covered with a hydroxypropylcellulose solution containing talc and magnesium stearate. The entericcoating layer consisting of methacrylic acid copolymer, mono- anddiglycerides, triethyl citrate and polysorbate was sprayed onto thepellets covered with a separating layer in a fluid bed apparatus. In afluid bed apparatus enteric coating layered pellets were coated with ahydroxypropyl methylcellulose solution containing magnesium stearate.The over-coating layered pellets were classified by sieving.

[0153] The enteric coating layered pellets with an over-coating layer,diclofenac-Na, MCC, polyvinylpyrrolidone cross-linked and sodium stearylfumarate were dry mixed and compressed into tablets using an excentertableting machine equipped with 11 mm punches. The amount of omeprazolein each tablet was approx. 10 mg and the amount of diclofenac-Na wasapprox. 50 mg. The tablet hardness was measured to 80 N.

Example 11

[0154] Fast disintegrating multipe unit tableted dosage form comprisingmagnesium omeprazole and piroxicam. Core material Magnesium omeprazole10.0 kg Sugar sphere seed 10.0 kg Hydroxypropyl methylcellulose  1.5 kgWater purified 29.9 kg Separating layer Core material 20.0 kgHydroxypropyl cellulose  2.0 kg Talc 3.43 kg Magnesium stearate 0.287kg  Water purified 41.0 kg Enteric coating layer Pellets covered withseparating layer 24.5 kg Methacrylic acid copolymer (30% suspension)32.7 kg Triethyl citrate 2.94 kg Mono-and diglycerides (NF) 0.49 kgPolysorbate 80 0.049 kg  Water purified 19.19 kg  Over-coating layerEnteric coating layered pellets 37.8 kg Hydroxypropyl methylcellulose0.49 kg Magnesium stearate 0.0245 kg  Water purified 11.6 kg Tabletsmg/tablet Overcoated pellets comprising omeprazole 94.9 Piroxicam 20.0Microcrystalline cellulose (MCC) 280 Polyvinylpyrrolidone cross-linked5.6 Sodium stearyl fumarate 0.56

[0155] Enteric coating layered pellets of magnesium omeprazole with anovercoating layer were prepared as in Example 10.

[0156] The enteric coating layered pellets with an over-coating layer,piroxicam, MCC, polyvinylpyrrolidone cross-linked and sodium stearylfumarate were dry mixed and compressed into tablets using an excentertableting machine equipped with 11 mm punches. The amount of omeprazolein each tablet was approx. 20 mg and the amount of piroxicam was approx.20 mg. The tablet hardness was measured to 110 N.

[0157] Results “Acid resistance” i.e. % left after exposure to 0.1 N HClfor 2 hrs Tablets Ex 1 95% Ex 2 95% Ex 3 99% Ex 4 91% Ex 5 92% Ex 6 96%Ex 7 93% Ex 10 91% Ex 11 91%

[0158] The best mode to practice the present invention is according tothe dosage forms of the types described in examples 5, 7 and 10.

[0159] The enteric coating layered pellets comprising a proton pumpinhibitor may also be prepared as described in the following examples.

Example 12

[0160] Preparation of enteric coating layered pellets byextrusion/spheronization. Core material Magnesium omeprazole 600 gMannitol 1000 g  Microcrystalline cellulose 300 g Hydroxypropylcellulose 100 g Sodium lauryl sulphate  6 g Water purified 802 gSeparating layer Core material (acc. to above) 400 g Hydroxypropylmethylcellulose  48 g Water purified 960 g Enteric coating layer Pelletscovered with separating layer (acc. to above) 200 g Methacrylic acidcopolymer 100 g Triethyl citrate  30 g Mono- and diglycerides (NF)  5 gPolysorbate 80  0.5 g  Water purified 309 g

[0161] Sodium lauryl sulphate is dissolved in purified water to form thegranulation liquid. Magnesium omeprazole, mannitol, microcrystallinecellulose and hydroxypropyl cellulose are dry-mixed. The granulationliquid is added to the powder mixture and the mass is wet-mixed.

[0162] The wet mass is forced through an extruder equipped with screensof size 0.5 mm. The extrudate is spheronized on a friction plate in aspheronizing apparatus. The core material is dried in a fluid bed dryerand classified. The prepared core material is covered by a separatinglayer in a fluid bed apparatus with a hydroxypropylmethylcellulose/water solution.

[0163] The enteric coating layer is applied to the pellets covered withseparating layer from an aqueous dispersion of methacrylic acidcopolymer plasticized with triethyl citrate to which a mono- anddiglycerides/polysorbate dispersion has been added. The pellets aredried in a fluid bed apparatus.

Example 13

[0164] Preparation of enteric coating layered pellets by powder layeringof sugar sphere seeds. Core material Magnesium omeprazole 1.500 g Sugarsphere seeds 1.500 g Hydroxypropyl methylcellulose   420 g Aerosil ®   8 g Water purified 4.230 g Separating layer Core material (acc. toabove)   500 g Hydroxypropyl cellulose   40 g Talc   67 g Magnesiumstearate    6 g Water purified   800 g Enteric coating layer Pelletscovered with separating layer (acc. to above)   500 g Methacrylic acidcopolymer   200 g Triethyl citrate   60 g Water purified   392 g

[0165] Magnesium omeprazole, part of the hydroxypropyl methylcelluloseand Aerosil® are dry-mixed forming a powder. Sugar sphere seeds(0.25-0.40 mm) are layered with the powder in a centrifugal fluidizedcoating granulator while spraying a hydroxypropyl methylcellulosesolution (6%, w/w).

[0166] The prepared core material is dried and covered by a separatinglayer in a centrifugal fluidized coating-granulator. A fluid bedapparatus is used for enteric coating layereing.

Example 14

[0167] Preparation of enteric coating layered pellets with cores ofsilicon dioxide seeds. Core material Magnesium omeprazole 8.00 kgSilicon dioxide 8.00 kg Hydroxypropyl methylcellulose 1.41 kg Sodiumlauryl sulphate 0.08 kg Water purified 28.00 kg  Separating layer Corematerial (acc. to above) 10.00 kg  Hydroxypropyl methylcellulose 0.80 kgWater purified 10.00 kg  Enteric coating layer Pellets covered withseparating layer (acc. to above)  300 g  Methacrylic acid copolymer  124g  Polyethylene glycol 400   25 g  Mono- and diglycerides (NF)   3 g Polysorbate 80   1 g  Water purified  463 g 

[0168] Suspension layering is performed in a fluid bed apparatus.Magnesium omeprazole is sprayed onto the silicon dioxide seeds from awater suspension containing the dissolved binder and a surface activeingredient.

[0169] The prepared core material is covered with a separating layer ina fluid bed apparatus with a hydroxypropyl methylcellulose solution. Theenteric coating layer consisting of methacrylic acid copolymer, mono-and diglycerides, polyethylene glycol 400 and polysorbate is sprayedonto the pellets covered with separating layer in a fluid bed apparatus.

Example 15

[0170] Preparation of enteric coating layered pellets. Enteric coatinglayer Pellets covered with separating layer 500 g (manufacturing andcomposition as in example 12) Methacrylic acid copolymer 250 gPolyethylene glycol 6000  75 g Mono- and diglycerides (NF) 12.5 g Polysorbate 80  1.2 g  Water purified 490 g

Example 16

[0171] Preparation of enteric coating layered pellets. Enteric coatingPellets covered with separating layer  500 g (manufacturing andcomposition as in example 1) Hydroxypropyl methylcellulose phthalate 250 g Cetanol  50 g Ethanol (95%) 1000 g Acetone 2500 g

Example 17

[0172] Preparation of enteric coating layered pellets. Core materialOmeprazole 225 g  Mannitol 1425 g  Hydroxypropyl cellulose 60 gMicrocrystalline cellulose 40 g Lactose anhydrous 80 g Sodium laurylsulphate  5 g Disodium hydrogen phosphate dihydrate  8 g Water purified350 g  Separating layer Core material (acc. to above) 300 g Hydroxypropyl cellulose 30 g Talc 51 g Magnesium stearate  4 g Entericcoating layer Pellets covered with separating layer (acc. to above) 300g  Methacrylic acid copolymer 140 g  Triethyl citrate 42 g Mono- anddiglycerides (NF)  7 g Polysorbate 80 0.7 g 

[0173] The dry ingredients for producing the core material are wellnixed in a mixer. Addition of granulation liquid is made and the mixtureis kneeded and granulated to a proper consistency. The wet mass ispressed through an extruder screen and the granules are converted into aspherical form in a spheronizer. The core material is dried in a fluidbed apparatus and classified into a suitable particle size range, e.g.0.5-1.0 mm. The prepared core material is covered with a separatinglayer and enteric coating layered as described in previous examples.

[0174] Preparation of active substance.

[0175] Magnesium omeprazole used in some of the examples is producedaccording to the process described in WO/95/01977, the singleenantiomers of omeprazole salts are prepared as described in WO/94/27988and omeprazole is produced according to the process disclosed in EP-A10005129. These documents are hereby incorporated in a whole byreference.

1. An oral pharmaceutical dosage form comprising an acid susceptibleproton pump inhibitor together with at least one Non SteroidalAntiinflammatory Drug (NSAID) and optionally pharmaceutically acceptableexcipients, characterized in that the dosage form is in the form of afixed unit dosage form comprising at least two pharmaceutically activecomponents, and wherein at least the proton pump inhibitor is protectedby an enteric coating layer.
 2. A dosage form according to claim 1,wherein the dosage form is a tablet formulation.
 3. A dosage formaccording to claim 1, wherein the dosage form is a capsule formulation.4. A dosage form according to claim 1, wherein the proton pump inhibitoris protected by two layers, an enteric coating layer and a layerseparating the enteric coating from the proton pump inhibitor.
 5. Adosage form according to claim 1, wherein the dosage form comprises aproton pump inhibitor and one NSAID.
 6. A dosage form according to claim1, wherein the proton pump inhibitor is omeprazole, an alkaline saltthereof, one of its single enantiomer or an alkaline salt thereof.
 7. Adosage form according to claim 6, wherein the proton pump inhibitor isS-omeprazole magnesium salt
 8. A dosage form according to claim 1,wherein the proton pump inhibitor is lansoprazole, or one of its singleenantiomers or a pharmaceutically acceptable salt thereof.
 9. A dosageform according to claim 1, wherein the proton pump inhibitor ispantoprazole, or one of its single enantiomers or a pharmaceuticallyacceptable salt thereof.
 10. A dosage form according to one of claims6-9, wherein the NSAID is ibuprofen, diclofenac, piroxicam or naproxen,or a pharmaceutical acceptable salt thereof.
 11. A dosage form accordingto one of claims 6-9, wherein the NSAID is diclofenac or piroxicam, orpharmaceutically acceptable salt thereof.
 12. A dosage form according toclaim 1, wherein the amount of proton pump inhibitor is in the range of10-80 mg and the amount of NSAID(s) is in the range of 10-800 mg.
 13. Adosage form according to claim 1, wherein the amount of proton pumpinhibitor is in the range of 10-40 mg and the amount of NSAID(s) is inthe range of 10-500 mg.
 14. A tableted dosage form according to claim 2,wherein the tablet consists of two separate layers, one layer comprisinga proton pump inhibitor and the other layer comprising one or moreNSAIDs.
 15. A tableted dosage form according to claim 2, wherein thetablet formulation is a multiple unit tableted dosage form comprisingthe proton pump inhibitor in the form of individually enteric coatinglayered pellets compressed together with NSAID comprising granules intoa tablet, whereby the enteric coating layer covering the individualpellets has mechanical properties such that the tableting of the pelletstogether with the NSAID comprising granules and optionallypharmaceutically acceptable excipients does not significantly affect theacid resistance of the individually enteric coating layered pellets. 16.A tableted dosage form according to claim 15, wherein the acidresistance of the enteric coating layered pellets is in coherence withthe requirements on enteric coating layered articles defined in theUnited States Pharmacopeia.
 17. A tableted dosage form according toclaim 15, wherein the acid resistance of the. enteric coating layeredpellets does not decrease more than 10% during the compression of thepellets into the multiple unit tableted dosage form.
 18. A tableteddosage form according to claim 15, wherein the enteric coating of theindividual pellets comprises a plasticized enteric coating layermaterial.
 19. A tableted dosage form according to claim 15, wherein theenteric coating layered pellets are-further covered with an over-coatinglayer comprising pharmaceutically acceptable excipients.
 20. A tableteddosage form according to claim 15, wherein the tablet is divisible. 21.A tableted dosage form according to claim 20, wherein the tablet isdispersible to an aqueous suspension comprising NSAID(s) and entericcoating layered pellets of a proton pump inhibitor.
 22. A tablet dosageform according to claim 2, wherein the tablet consists of two separatelayers, one layer comprising the proton pump inhibitor in the form ofenteric coating layered pellets compressed with tablet excipients into alayer, and the other layer gives an extended release of the incorporatedNSAID(s).
 23. A tablet dosage form according to claim 22, wherein thelayer comprising the NSAID(s) is a gelling matrix giving extendedrelease.
 24. A tableted dosage form according to claim 2, wherein thetablet is an enteric coating layered tablet comprising a mixture of theproton pump inhibitor and the NSAID comprising granules, optionallycomprising a water soluble or in water rapidly disintegrating separatinglayer in between the tablet core and the enteric coating layer.
 25. Atableted dosage form according to claim 2, wherein the tablet comprisingenteric coating layered pellets of the proton pump inhibitor compressedinto a tablet, which tablet is covered by a separate layer comprisingthe NSAID(s).
 26. A tableted dosage form according to claim 25, whereinthe tablet is covered by a pigmented tablet filmcoating layer.
 27. Atablet dosage form according to claim 2, wherein the tablet consists oftwo types of enteric coating layered pellets, one type comprises theproton pump inhibitor, and the other type comprises NSAID(s), togethercompressed with tablet excipients into a tablet.
 28. A tablet dosageform according to claim 2, wherein the tablet consists of entericcoating layered pellets comprising the proton pump inhibitor, andpellets comprising the NSAID(s) coating layered with an extended releasefilm, and these coating layered pellets are compressed with tabletexcipients into a tablet.
 29. A process for the manufacture of a fixeddosage form comprising a proton pump inhibitor and one or more NSAIDs ina capsule, characterized in that the proton pump inhibitor is preparedin the form of enteric coating layered pellets and that the pellets arefilled into a capsule together with prepared NSAID granules or entericcoating layered NSAID pellets, or NSAID pellets coating layered with anextended release film, optionally the mixture of pellets or granules aremixed with pharmaceutically acceptable excipients, and filled in acapsule.
 30. A process for the manufacture of a fixed dosage formcomprising a proton pump inhibitor and one or more NSAIDs in a multipleunit tableted dosage form, characterized in that the proton pumpinhibitor is prepared in the form of enteric coating layered pellets andthese pellets are mixed with prepared NSAID granules and optionallypharmaceutically acceptable tablets excipients whereafter the drymixture is compressed into a multiple unit tablet without giving anysignificant change of the acid resistance of the enteric coating layer.31. A process for the manufacture of a fixed dosage form comprising aproton pump inhibitor and one or more NSAIDs in a multiple unit tableteddosage form, characterized in that the proton pump inhibitor is preparedin the form of enteric coating layered pellets and the NSAID(s) isprepared in the form of coating layered pellets wherein the coatinglayer is an extended release layer or an enteric coating layer, and theprepared pellets are mixed with tablet excipients and compressed into atable.
 32. A process for the manufacture of a fixed dosage formcomprising a proton pump inhibitor and one or more NSAID(s) in anenteric coating layered tablet characterized in that the proton pumpinhibitor is admixed with the NSAID(s) and pharmaceutically acceptableexcipients whereafter the mixture is compressed into a tablet, and thetablet is covered with an enteric coating layer and optionally coveredwith a separating layer before the enteric coating layer is applied. 33.A method for the treatment of gastrointestinal side-effects associatedwith NSAID treatment in mammals and man by administering to a host inneed thereof a therapeutically effective dose of a multiple unittableted dosage form according to any of claims 1 to
 28. 34. A methodaccording to claim 33, wherein the disorder is an upper gastrointestinaldisorder associated with NSAID treatment.
 35. Use of a dosage formaccording to any of claims 1 to 28 for the manufacture of a medicamentfor treatment or prevention of gastro intestinal side-effects associatedwith NSAID(s) treatment disorders.
 36. Use according to claim 35 whereinthe disorder is an upper gastrointestinal disorder associated with NSAIDtreatment.